The function of the nervous system depends on the appropriate specification of neurotransmitters and their receptors that enable the function of neural circuits. We have discovered that circuit activity plays a key role in transmitter specification (Dulcis and Spitzer, 2008; Dulcis et al., 2013) and that changes in transmitter expression are matched by corresponding changes in postsynaptic receptors (Borodinsky & Spitzer, 2007; Dulcis & Spitzer, 2008; Dulcis et al., 2013), causing changes in behaviors. We now propose to determine whether neurotransmitter switching can be induced by patterns of neuronal activity that induce LTP in the adult rat hippocampus, and whether this is accompanied by changes receptor population. We will also determine whether environmental enrichment and fear conditioning that engage the hippocampus induce neurotransmitter switching. We will test the role of newly expressed transmitters in adult neurogenesis and in the development of resilience to acute and chronic stress. The immediate goal of this research is to test the hypothesis that activation of neural circuits in the hippocampus leads to transmitter respecification in neurons in these circuits, with corresponding changes in adult neurogenesis and/or stress behavior. A long-term goal is to understand how neural network activation can be used to induce neurotransmitter plasticity in the adult brain and ultimately to advance the mission of the NIH to treat neurological disorders.